Active maternal smoking during pregnancy is associated with adverse health effects for the infant at birth and throughout childhood. Only recently, however, has it been appreciated that involuntary passive cigarette smoke exposure of the pregnant woman (via household or work environmental exposures) may also be associated with adverse effects on fetal health and development. The present proposal is unique in representing the first programmatic attempt, in an animal model, to investigate the long-term consequences of passive maternal smoking during pregnancy on the conceptus. Using reference cigarettes with established smoke constituents to create clinically relevant conditions of sidestream smoke, as well as biological monitoring of smoke exposures, this proposal offers the following hypothesis: Passive maternal smoking during pregnancy has adverse effects on the neurobehavioral development of the fetus (as manifest in cognitive dysfunction) and these effects are caused by structural and functional disruption of the hippocampus. The specific aims of the program are: 1) To establish the nature and extent of cognitive dysfunction which occurs in the offspring following passive maternal cigarette smoking during pregnancy. Cognitive processes in the rodent will be evaluated via complex spatial and non-spatial tasks known to be sensitive indicators of hippocampal pathology. These studies will identify dose-response functions, critical exposure periods, and dissociations of specific cognitive deficits from sensory or motor impairments. 2) To establish the nature and extent of the structural alterations in the hippocampus which occur following passive maternal smoking during pregnancy. Quantitative neuroanatomical measurements, synthetic enzyme activity, and receptor autoradiography will be utilized to determine the structural integrity of the hippocampus. The hippocampus mediates spatial information processing in rodents and is also known to be highly susceptible to irreversible cytotoxic damage by moderate hypoxic episodes of varied origin. 3) To determine the relationship between the integrity of the hippocampus and the cognitive dysfunction using pharmacological probes. The functional integrity of two extrinsic neural pathways that project to the hippocampus (cholinergic & noradrenergic) and one intrinsic transmitter system (GABAergic) will be probed using selected pharmacological agonists and antagonists with the aim of predictively modifying the rats' behavior in spatial learning tasks. The goals of the current proposal are to quantitatively define the relationship between passive maternal smoke exposure during pregnancy and cognitive development of the offspring, and to identify characterize the neurobiological mechanism(s) underlying this cognitive deficit.